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Histidine re-sensitizes acute lymphoblastic leukemia cells to 6-mercaptopurine through tetrahydrofolate consumption and SIRT5-mediated desuccinylation

ABSTRACT: Given the progressive improvements in the efficacy of multiagent chemotherapy and the survival rate of pediatric acute lymphoblastic leukemia (ALL), concerted efforts are required to eradicate chemoresistance-induced disease progression and relapse. Our present study coupled chemoresistance in B-ALL with histidine metabolism deficiency. We provide evidence that histidine supplementation significantly shifts the 6-MP dose response in 6-MP-resistant B-ALL cell lines and xenograft mice model. Moreover, we prove that the THF consumption through histidine degradation pathway and SIRT5-mediated desuccinylation of HINT1 are required for the histidine combination therapy to promote B-ALL cells against 6-MP resistance. Collectively, our results demonstrated that histidine supplementation and SIRT5-HINT1 axis activators might be rational strategies to overcome chemoresistance, thus protect B-ALL patients from disease progression or recurrence.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236934 | GEO | 2023/07/27

REPOSITORIES: GEO

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Histidine re-sensitizes acute lymphoblastic leukemia cells to 6-mercaptopurine through tetrahydrofolate consumption and SIRT5-mediated desuccinylation

Project description:Histidine re-sensitizes acute lymphoblastic leukemia cells to 6-mercaptopurine through tetrahydrofolate consumption and SIRT5-mediated desuccinylation

| PRJNA993153 | ENA

Histidine re-sensitizes pediatric acute lymphoblastic leukemia to 6-mercaptopurine through tetrahydrofolate consumption and SIRT5-mediated desuccinylation.

Project description:Despite progressive improvements in the survival rate of pediatric B-cell lineage acute lymphoblastic leukemia (B-ALL), chemoresistance-induced disease progression and recurrence still occur with poor prognosis, thus highlighting the urgent need to eradicate drug resistance in B-ALL. The 6-mercaptopurine (6-MP) is the backbone of ALL combination chemotherapy, and resistance to it is crucially related to relapse. The present study couples chemoresistance in pediatric B-ALL with histidine metabolism deficiency. Evidence was provided that histidine supplementation significantly shifts the 6-MP dose-response in 6-MP-resistant B-ALL. It is revealed that increased tetrahydrofolate consumption via histidine catabolism partially explains the re-sensitization ability of histidine. More importantly, this work provides fresh insights into that desuccinylation mediated by SIRT5 is an indispensable and synergistic requirement for histidine combination therapy against 6-MP resistance, which is undisclosed previously and demonstrates a rational strategy to ameliorate chemoresistance and protect pediatric patients with B-ALL from disease progression or relapse.

| S-EPMC10940622 | biostudies-literature

Role of SIRT5 in Inhibition of Myocardial Hypertrophy

Project description:SIRT5 is one of the seven members of the NAD+-dependent sirtuin family of protein deacylase that is mainly present in mitochondria and regulates metabolism. In heart, SIRT5 is highly expressed and responsible for succinylation on metabolic enzymes. Although the role of SIRT5 in maintaining cardiac homeostasis under physiological stress and few potential substrates of SIRT5 have been preliminarily revealed, the regulatory network and key cellular signaling pathways involving SIRT5 in myocardial hypertrophy remain largely unknown. Here, we used an established murine model of pressure overload-induced myocardial hypertrophy caused by transverse aortic constriction (TAC) to outline the network and pathway involving SIRT5 in cardiac stress responses. Remarkably, SIRT5 KO mice had enhanced myocardial hypertrophy after TAC surgery compared with wild-type mice.

2024-10-05 | GSE186985 | GEO

RNA-seq of SIRT5-KO cells infected with SARS-CoV-2

Project description:We are studying the role of human sirtuin SIRT5 during viral infection with SARS-CoV-2. We performed RNA-sequencing of WT and SIRT5-KO human lung adenocarinoma A549 cells overexpressing ACE2 (A549-ACE2), in infected and mock-infected conditions. . Our analysis revealed that SARS-CoV-2 replication is attenuated in SIRT5-KO cells. In addition, SIRT5-KO cells expressed higher basal levels of innate immunity markers and mounted a stronger antiviral response. Our results indicate that SIRT5 is a proviral factor necessary for efficient viral replication.

2021-11-10 | GSE188382 | GEO

The deacylase SIRT5 supports melanoma viability by regulating chromatin dynamics.

Project description:Cutaneous melanoma remains the most lethal skin cancer, and ranks third among all malignancies in terms of years of life lost. Despite the advent of immune checkpoint and targeted therapies, only roughly half of patients with advanced melanoma achieve a durable remission. SIRT5 is a member of the sirtuin family of protein deacylases that regulate metabolism and other biological processes. Germline Sirt5 deficiency is associated with mild phenotypes in mice. Here we show that SIRT5 is required for proliferation and survival across all cutaneous melanoma genotypes tested, as well as uveal melanoma, a genetically distinct melanoma subtype that arises in the eye, and is incurable once metastatic. Likewise, SIRT5 is required for efficient tumor formation by melanoma xenografts, and in an autochthonous mouse Braf;Pten-driven melanoma model. Via metabolite and transcriptomic analyses, we find that SIRT5 is required to maintain histone acetylation and methylation levels in melanoma cells, thereby promoting proper gene expression. SIRT5-dependent genes notably include MITF, a key lineage-specific survival oncogene in melanoma, and the c-MYC proto-oncogene. SIRT5 may represent a novel, druggable genotype-independent addiction in melanoma.

2021-05-07 | GSE169205 | GEO

RNA Profiles of the Korat Chicken Breast Muscle with Increased Carnosine Content Produced through Dietary Supplementation with β-Alanine or L-Histidine

Project description:Carnosine is a bioactive food component with several potential health benefits for humans due to its physiological functions. Dietary　supplementation with β-alanine or L-histidine can increase the carnosine content of skeletal muscles in chickens. Dietary supplementation with β-alanine or L-histidine has produced a slow-growing chicken variety　with high carnosine content in the breast meat; however, the　supplementation with L-histidine alone softens the meat toughness, which may affect consumers’ willingness to buy the meat. Gene　expression is a key factor that influences meat quality. Understanding the molecular mechanisms that affect carnosine content and meat toughness would allow the production of more value-added slow-growing chickens. We compared global gene expression in chicken breast muscles with differing carnosine contents and meat toughness produced through dietary supplementation with β-alanine or L-histidine. We identified differentially expressed genes involved in regulating myosin, collagen, intramuscular fat, and calpain—factors that may affect meat tenderness. Pathway enrichment analysis indicated that the insulin-related and adipocytokine signaling pathways were altered by dietary supplementation with β-alanine or L-histidine. These data will be useful for future studies on carnosine content and meat toughness in slow-growing chickens.

2021-09-04 | GSE179643 | GEO

SIRT5 loss promotes hepatocarcinogenesis via bile acid-induced immunosuppressive microenvironment

Project description:Hepatocellular carcinoma (HCC) is a prototypical inflammation-associated cancer and the tumor microenvironment (TME) plays a pivotal role in HCC pathogenesis and response to therapy. The liver is a metabolically active organ, but how liver metabolism impacts TME during HCC development and response to immunotherapy are poorly understood. Here, we show that the metabolic regulator SIRT5 is downregulated in human primary HCC samples, and that Sirt5 deficiency in mice synergizes with oncogenes to increase bile acid (BA) production, which is due to hypersuccinylation and increased BA biosynthesis in the peroxisome. BA acts as a cell-signaling mediator to stimulate its nuclear receptor and promotes M2-like macrophage polarization, thereby creating an immunosuppressive microenvironment favorable for HCC initiating cells. Furthermore, high serum taurocholic acid, a major primary BA, correlates with low SIRT5 expression and increased M2-like tumor-associated macrophages (TAMs) in liver tissue samples from HCC patients. Importantly, administration of cholestyramine, a BA sequestrant and FDA-approved medication for hyperlipemia, reverses the effect of Sirt5 deficiency on promoting M2-like polarized TAMs and liver tumor growth. Our study thus uncovers a novel function of SIRT5 in orchestrating BA metabolism to prevent tumor immune evasion and suppress HCC. These results also suggest a potential strategy using clinically proven bile acid sequestrants for the treatment of HCC patients, especially those with decreased SIRT5 and abnormally high BAs.

2022-01-10 | GSE193213 | GEO

WGS histidine overproducers

Project description:Whole genomes sequencing to determine mutations in histidine overproducers generated with a toxic histidine analog

| PRJEB45772 | ENA

Histidine supplementation can escalate or rescue HARS deficiency in a Charcot Marie Tooth Disease model

Project description:Aminoacyl-tRNA synthetases (ARSs) are essential enzymes responsible for charging amino acids onto cognate tRNAs during protein synthesis¬. In histidyl-tRNA synthetase (HARS), autosomal dominant mutations in the HARS catalytic domain are associated with Charcot Marie Tooth Disease Type 2W (CMT2W), while anticodon-binding domain mutations cause Usher Syndrome Type IIIB (USH3B). We use yeast as a model system to study disease-causing HARS mutations (V133F, V155G, Y330C, S356N) associated with CMT2W, and Y454S, associated with USH3B. All human HARS variants complemented genomic deletion of the yeast ortholog HTS1 at high expression levels. CMT2W associated mutations, but not Y454S, result in reduced growth. HARS V155G and S356N cause accumulation of insoluble proteins and mistranslation in yeast, and the growth defect of these mutants was rescued by histidine addition to the growth media, restoring the soluble proteome. V133F and Y330C, on the other hand, lead to decreased HARS abundance. Histidine supplementation further reduced viability in yeast expressing V133F and Y330C, and lead to insoluble protein accumulation, indicating histidine toxicity associated with these mutants. Because histidine is in clinical trials as treatment for USH3B, our data will inform future treatment options for these as well as CMT patients, where histidine supplementation may either have a toxic or compensating effect dependingon the nature of the causative HARS variant.

2023-03-10 | PXD034865 | Pride

Deglutarylation of GCDH by SIRT5 controls lysine metabolism in mice

Project description:A wide range of protein acyl modifications has been identified on enzymes across various metabolic processes; however, the impact of these modifications remains poorly understood. Protein glutarylation is a recently identified modification that can be non-enzymatically driven by glutaryl-CoA. In mammalian systems, this unique metabolite is only produced in the lysine and tryptophan oxidative pathways. To better understand the biology of protein glutarylation, we studied the relationship between enzymes within the lysine/tryptophan catabolic pathways, protein glutarylation, and regulation by the deglutarylating enzyme Sirtuin 5 (SIRT5). Here, we identify glutarylation of the lysine oxidation pathway enzyme glutaryl-CoA dehydrogenase (GCDH). We show increased GCDH glutarylation when glutaryl-CoA production is stimulated by lysine catabolism. Our data reveal glutarylation of GCDH impacts its function, ultimately decreasing lysine oxidation. We then demonstrate the ability of SIRT5 to deglutarylate GCDH, restoring its enzymatic activity. Finally, metabolomic and bioinformatic data indicate a novel role for SIRT5 in regulation of amino acid metabolism. Together, these data suggest a model whereby a feedback loop exists within the lysine/tryptophan oxidation pathway, in which glutaryl-CoA is produced, in turn inhibiting GCDH function. This inhibition is relieved by SIRT5 deacylation activity.

2022-02-21 | PXD018156 | Pride

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